The present invention relates to implantable analyte sensors.
Several implantable glucose sensors have been developed. Examples include those described in U.S. Pat. Nos. 5,387,327; 5,411,647; and 5,476,776; as well as those described in PCT International Publication numbers WO 91/15993; WO 94/20602; WO 96/06947; and WO 97/19344. The implantable glucose sensors usually include a polymer substrate, with metal electrodes printed on the surface of the substrate. A biocompatible membrane covers the electrodes, allowing glucose to reach the electrodes, while excluding other molecules, such as proteins. Electrochemistry, often with the aid of enzymes at the electrodes, is used to determine the quantity of glucose present. The glucose sensor is implanted into a patient, and the electrodes may be attached via wires that pass out of the patient""s body to external circuitry that controls the electrodes, measures and reports the glucose concentration. Alternatively, all or part of this external circuitry may be miniaturized and included in the implantable glucose sensor. A transmitter, such as that described in WO 97/19344, may even be included in the implantable glucose sensor, completely eliminating the need for leads that pass out of the patient.
A problem associated with an amperometric glucose sensor is unstable signals. This may result from degradation of the enzyme from interaction with protein, leakage of the enzyme, and/or fouling of the electrode. The usual way to overcome this is to use the above described biocompatible membrane, or a coating. However, several problems are also associated with these membranes. For example, Nation-based biosensor membranes exhibit cracking, flaking, protein adhesion, and calcium deposits. Mineralization of polymer-based membranes occurs in the biological environment, resulting in cracking and changes in permeability. The tortuous porosity associated with polymer membranes has also been shown to be important in membrane stability and mineralization in vivo. Biological components, which enter pores or voids in the material, cause metabolic shadows, which are loci for ion and calcium accumulation. This situation, coupled with the fact that mineral deposits have been known to propagate surface fractures in polymeric membranes, presents a potentially serious problem for implantable glucose sensors.
In polymer membranes the pore size distribution usually follows some kind of probability distribution (e.g. gaussian), which leaves a finite probability for large proteins to eventually transfer through the membrane. Drift may be caused by this leakage or inadequate diffusion properties, and events at the body-sensor interface such as biofouling and protein adsorption, encapsulation with fibrotic tissue, and degradation of the device material over time.
Currently, membranes with nominal pore sizes as small as 20 nm are available. Even so, the filtration at these dimensions is far from absolute. The most common filters are polymeric membranes formed from a solvent-casting process, which result in a pore size distribution with variations as large as 30%. The use of ion-track etching to form membranes (e.g. MILLPORE ISOPORE) produces a much tighter pore size distribution (xc2x110%). However, these membranes have low porosities ( less than 109 pores/cm2), limited pore sizes, and the pores are randomly distributed across the surface. Porous alumina (e.g. WHATMAN) has also been used to achieve uniform pores. Although the aluminas typically have higher pore densities ( greater than 1010/cm2), only certain pore sizes (typically greater than 20 nanometers) can be achieved and the pore configurations and arrangements are difficult to control.
In one aspect, the present invention is an implantable analyte sensor, comprising a substrate, electrodes on the substrate, and a membrane on the electrodes. The membrane has a glucose diffusion test result of at least 1 mg/dl in 330 min., and an albumin diffusion test result of at most 0.1 g/dl in 420 min. and can comprise elemental silicon.
In another aspect, the present invention relates to a method of making an implantable analyte sensor, comprising covering electrodes with a membrane. The electrodes are on a substrate, and the membrane has a glucose diffusion test result of at least 1 mg/dl in 330 min., and an albumin diffusion test result of at most 0.1 g/dl in 420 min. The membrane can comprise elemental silicon.